tbuckley/cabot-search huggingface dataset:
Abstract 3288: A novel and defined TLR3 agonist based anticancer therpay
Authors: Dongho Kim, Sungwhan Lee
Journal: Cancer Research (2023)

Abstract Synthetic dsRNA analogs recognized by TLR3 are an attractive adjuvant candidate for fight against intracellular pathogens or tumors, because of their enhanced T cell-mediated and humoral immunities. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been severely limited due to heterogenicity, inconsistent activity, poor stability, and toxicity. In spite of numerous clinical trials, few products have been approved for human use. To overcome these limitations, we try to develop a novel defined form of TLR3 agonist. A single 275-kDa homogeneous molecule was selected as an alternative of poly IC and its derivatives and named NexaVant (NVT). The analytical analyses including reverse phase-HPLC analysis demonstrated that NVT is homologous without a lot-to-lot variation. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without signs of serious toxicity. NVT increases the expression of dsRNA sensors such as TLR3, MDA-5, and RIG-I. Together with a potent apoptotic cell death to several cancer cell lines, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-alpha production. Several poly IC and its derivatives are used as a in situ anticancer agent in clinical trials. NexaVant was tested as an in-situ cancer therapy reagent in several animal models. When NVT is injected into tumors, it induces and recruits diverse immune cells with a potent anti-cancer effect. Combined with anit-PD-1 antibody, it shows the increase number of DC and T-cells, especially CD8 T cells and decrease that of Tregs. Using human PD-1 knock-in mouse model, NVT has shown the synergistic anti-cancer effect with anti-PD-1 antibody. Several animal efficacy data target to head and neck cancer, triple-negative breast cancer, and melanoma would be presented. Citation Format: Dongho Kim, Sungwhan Lee. A novel and defined TLR3 agonist based anticancer therpay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3288.
Abstract 2325: IRF1 displays opposing tumor cell-intrinsic and -extrinsic roles in anti-tumor immunity
Authors: Prabhat Kumar Purbey, Manash K. Paul, Keisuke S. Iwamoto, Allison Daly, Joowon Seo, Ameya S. Champhekar, Katie Campbell, Dorthe Schaue, William H. McBride, Steven M. Dubinett, Antoni Ribas, Stephen T. Smale, Philip O. Scumpia
Journal: Cancer Research (2023)

Abstract Interferons (IFNs), including IFN-α/β and IFN-γ, are multifaceted cytokines critical for antitumor immunity but contribute to T cell exhaustion through immune checkpoints. Recently, tumor cell expression of IRF1 was shown to enhance antitumor immunity, but a comprehensive evaluation of how IRF1 regulates IFN responses in the tumor and host has not been performed. Here, we show that Irf1-/- mice display enhanced tumor growth of WT and Irf1-/- tumors, as they fail to recruit sufficient NK cells and cytotoxic T cell (CTL). However, Irf1-/- tumors in wild-type mice displayed rapid immunogenic control, expansion of intratumoral lymphoid cells with enhanced effector programs and diminished exhaustion programs when compared to WT tumors. Mechanistically, IRF1 positively regulates the expression of distinct subsets of anti-tumor immunity suppression genes including the CD274/PD-L1, TRAIL, and IDO-1 checkpoints but not the IFN-inducible chemokines CXCL9-11. Surprisingly, control of Irf1-/- tumors required host IFN-α/β signaling but not IFN-γ signaling, while PD-L1 overexpression only weakly restored tumor growth. Thus, IRF1 selectively regulates the effects of IFNs on tumor cells and the tumor microenvironment and may be targeted to boost anti-tumor immunity. Citation Format: Prabhat Kumar Purbey, Manash K. Paul, Keisuke S. Iwamoto, Allison Daly, Joowon Seo, Ameya S. Champhekar, Katie Campbell, Dorthe Schaue, William H. McBride, Steven M. Dubinett, Antoni Ribas, Stephen T. Smale, Philip O. Scumpia. IRF1 displays opposing tumor cell-intrinsic and -extrinsic roles in anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2325.
Abstract 4504: Targeting cMYC in metastatic castration resistant and neuroendocrine prostate cancer
Authors: Chidiebere U. Awah, Olorunseun O. Ogunwobi
Journal: Cancer Research (2023)

Abstract Prostate cancer is the most common cancer in men and the second leading cause of cancer death among men in the United States according to the National Cancer Institute. Current treatment modalities involve prostatectomy, androgen receptor blockade and supportive/palliative care. Despite these treatment options, metastatic castration resistant prostate cancer and neuroendocrine prostate cancer still have very dismal clinical outcomes. Therefore, there is a need to understand the biology of the aggressive prostate cancer subtypes to identify novel targetable molecules. The castration resistant prostate cancer, neuroendocrine prostate cancer and the metastatic prostate cancers that recur have c-MYC amplification. These cancers are not responsive to androgen blockade or deprivation therapy. Attempts to target c-MYC have been difficult due to the intrinsic disordered nature of c-MYC. Various approaches have been attempted to control c-MYC; namely RNAi which has high off target effects, anti-sense oligonucleotides (ASO) which have low cellular penetrance and needs phosphorothioate modification, G-quadruplex inhibitors which are unspecific as they block POLII, the BRD4 and CDK inhibitors which are indirect inhibitors of c-MYC. Only OmoMyc a bHLH domain mutant with enhanced leucine zipper dimerization is in phase 1 trials with limited bioavailability. To explore the possibility of targeting c-MYC in these difficult-to-treat prostate cancers, we transfected C4-2B, a cellular model of metastatic castration resistant prostate cancer, with engineered destabilized 3‘UTR AU rich element of c-MYC. We found that we degraded c-MYC transcript and protein and killed the cancer cells. Taken together, we offer preliminary evidence that we can directly target c-MYC and inhibit these difficult-to-treat cancers. In vivo studies to validate these findings are ongoing. Citation Format: Chidiebere U. Awah, Olorunseun O. Ogunwobi. Targeting cMYC in metastatic castration resistant and neuroendocrine prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4504.
Abstract 3739: MAFG promotes melanomagenesis through the transcriptional regulation of hypoxic and immune responses
Authors: Olga Vera, Michael Martinez, Florian A. Karreth
Journal: Cancer Research (2023)

Abstract The small MAF family of transcription factors, consisting of MAFG, MAFF, and MAFK, dimerize with CNC/BACH proteins to regulate diverse transcriptional programs. Previously, we have shown that miRNA-29 suppresses melanoma development, at least in part, by repressing MAFG expression. Moreover, analysis of the TCGA revealed frequent copy number gains and/or overexpression of MAFG in melanoma. However, whether MAFG has oncogenic effects in and is critical for melanoma is unknown. We found that silencing of MAFG, but not MAFF or MAFK, abrogates growth of melanoma cells in vitro, while melanocyte cell lines are less reliant on MAFG. Conversely, MAFG overexpression promoted proliferation and focus formation of human melanocyte and melanoma cell lines. Using a high-throughput melanoma mouse modeling (ESC-GEMM) platform, we found that in vivo overexpression of MAFG in BRAFV600E; PTEN+/- mice potently accelerated melanoma development. RNA-sequencing revealed that MAFG regulates transcriptional programs associated with hypoxic and immune responses. Accordingly, MAFG overexpressing cells exhibited better ability to survive under hypoxic conditions, probably through the regulation of HIF1A. Moreover, MAFG overexpressing cells showed increased expression of cytokines of the of the C-C chemokine family, CCL3 and CCL5. MAFG overexpressing tumors from ESC-GEMM mice and MAFG-High melanomas from TCGA had features of immune-cold milieus, characterized by reduced infiltration of CD45+ immune cells and CD8+ T cells. Altogether, we demonstrate that MAFG promotes melanomagenesis, in part, by regulating the response to hypoxic conditions and chemokine expression, which may rewire the tumor immune microenvironment. Citation Format: Olga Vera, Michael Martinez, Florian A. Karreth. MAFG promotes melanomagenesis through the transcriptional regulation of hypoxic and immune responses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3739.
Abstract 2575: A multi-omic screening approach identifies the E3-ubiquitin ligase DCAF13 as a novel vulnerability in lung adenocarcinoma
Authors: Vinona T. Wagner, Yun-Chien Chang, Piero Giansanti, Rupert Öllinger, Thomas Engleitner, Bernhard Kuster, Florian Bassermann
Journal: Cancer Research (2023)

Abstract Lung adenocarcinoma (LuAD) is the most prevalent subtype of lung cancer but despite advances in targeted therapy approaches, LuAD patients still have a 5-year survival rate of less than 15%. This is largely owed to a high variability in cancer driver mutations, with only around 25% of patients being eligible for targeted therapy, highlighting the need for therapy approaches beyond the level of genetic modifications. In order to determine novel vulnerabilities of LuAD, we performed a CRISPR/Cas9-based genomic screen with a pooled sgRNA library targeting genes of the ubiquitin system. The screen identified the poorly characterized E3-ubiquitin ligase DCAF13 as an essential gene for LuAD cell survival. Data mining of LuAD patient data revealed that DCAF13 is significantly overexpressed in tumor versus normal tissue and that high DCAF13 expression correlates with adverse overall survival and progression free survival. Mechanistically, DCAF13 depletion leads to a decrease in cell proliferation and subsequent cell death, which can be rescued by apoptosis inhibition. Immunofluorescence revealed that DCAF13 localizes to the centrosome, cell-cell contacts and the nucleus of LuAD cells, indicating a potential role in transcription control. Functionally, DCAF13 is a predicted substrate recruiting unit of a CUL4-family ubiquitin ligase. Indeed, we show that DCAF13 binds to CUL4B and DDB1 to form an active ubiquitin ligase complex. In an effort to identify lung cancer specific relevant ubiquitylation substrates of DCAF13, we performed affinity-based interactome screens and non-affinity-based functional proteomics in LuAD cells. Cross-validation of these approaches revealed distinct tumor-suppressive transcription factors, which are known to play a role in tumorigenesis, embryogenesis and stem cell differentiation. Ongoing biochemical and transcriptomic analyses further determine the involvement of these transcription factors and DCAF13 in the establishment and maintenance of LuAD. Taken together, we nominate DCAF13 as a novel vulnerability in LuAD with potential implication in future targeted therapy strategies. Citation Format: Vinona T. Wagner, Yun-Chien Chang, Piero Giansanti, Rupert Öllinger, Thomas Engleitner, Bernhard Kuster, Florian Bassermann. A multi-omic screening approach identifies the E3-ubiquitin ligase DCAF13 as a novel vulnerability in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2575.
Abstract 3169: Decoupling the correlation between cytotoxic and exhausted T lymphocyte transcriptomic signatures in melanoma enhances immunotherapy response prediction
Authors: Binbin Wang, Kun Wang, Peng Jiang, Eytan Ruppin
Journal: Cancer Research (2023)

Abstract Background: Cytotoxic T lymphocytes (CTL) play a crucial role in anti-cancer immunity. Progression of CTL to exhausted T lymphocytes (ETL) that overexpress inhibitory receptors can substantially decrease effector cytokines production and diminish cytolytic activity in tumor microenvironment (TME). However, while the activity levels of CTL and ETL are considered important determinants of immune checkpoint inhibitors (ICIs) response, it has been repeatedly observed that their predictive power is quite limited. Studying this conundrum on a large scale across the TCGA cohort, we find that ETL and CTL activity (estimated based on conventional gene signatures in the bulk tumor expression) is strongly positively correlated in most cancer types. We thus hypothesized that their limited predictive power may arise due to this high expression concordance, such that their opposing associations with response effectively cancel each other. Methods and Results: Aiming to find conditions where the association between these CD8+ T cell states and ICIs response is enhanced, we analyzed TCGA melanoma bulk gene expression via an interaction linear regression model to identify a set of genes whose expression diminishes the CTL and ETL correlation as much as possible. We further tested this decoupling signature (DS) in several independent melanoma bulk expression ICIs cohorts, showing that in high-DS patients, the correlation between ETL and CTL activities is indeed markedly lower than in the low-DS patient groups. Second, this successful decoupling now increases the power of CTL activity in predicting ICIs response in high DS patients, making it superior to other state-of-art ICIs prediction transcriptomic signatures. Significance: These results demonstrate the utility of a new decoupling score for boosting the power of CTL activity in predicting ICIs response in melanoma. Citation Format: Binbin Wang, Kun Wang, Peng Jiang, Eytan Ruppin. Decoupling the correlation between cytotoxic and exhausted T lymphocyte transcriptomic signatures in melanoma enhances immunotherapy response prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3169.
Abstract 5093: Chemically inducible splice-neoantigens for cancer immunotherapy
Authors: Shingo Matsushima, Masahiko Ajiro, Kei Iida, Kenji Chamoto, Tasuku Honjo, Masatoshi Hagiwara
Journal: Cancer Research (2023)

Abstract Although immune checkpoint blockade therapies have dramatically improved the survival rate of patients with cancer compared with other treatment approaches, a substantial number of patients show poor response or resistance to these therapies. Meta-analyses for programmed cell death 1 (PD-1) blockade responses highlight the importance of neoantigens, derived from non-synonymous mutations in cancer cells, for antitumor immune responses. Intriguingly, recent transcriptome and genomics studies predict the presence of putative neoantigens as a result of an irregular pre-mRNA splicing regulation in cancer cells, indicating that alterations in RNA splicing in cancer cells might induce antitumor immune responses. Here, we report that induction of serine/arginine-rich splicing factor (SRSF)-dependent splicing boosts the production of splicing-associated neoantigens (splice-neoantigens) and potentiates the response to PD-1 blockade. Administration of a synthetic SRSF activator RECTAS suppressed tumor growth in a host CD8+ T cell- and tumor major histocompatibility complex class I-dependent manner and promoted the antitumor effect of anti-PD-L1 antibody without detectable autoimmunity. Subsequent transcriptome analysis and validation for immunogenicity identified six splice-neoantigen candidates whose expression was induced by RECTAS treatment. Importantly, vaccination of the identified neoepitopes elicited T cell responses capable of killing cancer cells in vitro, in addition to suppression of tumor growth in vivo upon sensitization with RECTAS. Collectively, these results provide support for the further development of splice variant-inducing treatments for cancer immunotherapy. Citation Format: Shingo Matsushima, Masahiko Ajiro, Kei Iida, Kenji Chamoto, Tasuku Honjo, Masatoshi Hagiwara. Chemically inducible splice-neoantigens for cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5093.
Abstract 2340: Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer
Authors: Guohuang Fan, Jianfei Wang, Na Wang, Yuanyuan Zhang, Yong Zhang, Binle Tian, Xuebing Jia
Journal: Cancer Research (2023)

Abstract Within the tumor microenvironment (TME), regulatory T (Treg) cells are one attractive cell type for targeting as they play a critical role in immunosuppression. Therapeutic strategies that specifically inhibit tumor-infiltrating Tregs while sparing peripheral and normal tissue Tregs are highly desirable. The tumor-associated Tregs express the chemokine receptor CCR8, which plays a role in the induction, expansion, chemotactic migration, and immunosuppression of tumor-associated Tregs. Thus, targeted inhibition of CCR8 is a potential therapeutic strategy against cancer. We have developed a monoclonal antibody antagonist of CCR8, IPG0521, which potently inhibited the receptor-mediated signaling and chemotaxis in Treg cells with single digital nanomolar IC50. RNA sequencing (RNA-seq)analysis indicated that CCL1-induced up-regulation of immunosuppressive genes, including PD-1, CTLA4, IL-10, TIGIT etc., were reversed by IPG0521 in tumor-derived Treg cells. IPG0521 potently inhibited the growth of multiple tumor types in both syngeinic and immune-humanized mouse models, including lung cancer, liver cancer, breast cancer, via inhibiting Treg and activating CD8+ T cells. These data pave the way for the development of IPG0521, which is under IND filing, as a novel therapeutic agent against cancer. Citation Format: Guohuang Fan, Jianfei Wang, Na Wang, Yuanyuan Zhang, Yong Zhang, Binle Tian, Xuebing Jia. Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2340.
Abstract 999: Colocalization of MAGE-A3 and MAGE-A4 in bladder cancer
Authors: Bailey Gilmore, Rachel Gonzalez, Aubrey Su, Dehe Kong, Eden Zewdu, Jina Yom, Tianli Qu, Zhaoying Guo, Xiaomin Hu, Qi Ren, Ranran Zhang, Eric Christenson, Yan Ma, Dezhong Yin, Patrick Yin, Wei Fu, Xuan Liu, Krishnan Allampallam
Journal: Cancer Research (2023)

Abstract The treatment of bladder cancers has improved with new immunotherapy such as PD-L1. However, not all bladder cancers respond to PD-L1 immunotherapy which is why new targets are being assessed. Melanoma-associated antigen gene A (MAGE-A) family proteins are expressed in a variety of tumors, with each MAGE-A protein having unique roles in cancer pathogenesis. One advantage of targeting MAGE-A family members is the lack of expression in normal tissues which makes them well-suited for targeted cancer immunotherapy. The challenge with screening the MAGE-A family is to find a specific antibody since the 12-member family has over 60% sequence in homology. In this study, we evaluate multiple MAGE-A3 and MAGE-A4 antibodies using CytoSections, a reproducible alternative to control tissue with an expression of target biomarkers. A series of antibodies specific to each MAGE-A3 and MAGE-A4 protein were discovered and used to screen twenty-five bladder cancer tissues. The results showed that MAGE-A3 was present in 9 of the 25 bladder cancers, while MAGE-A4 was present in 10 of the 25 bladder cancers evaluated; in the meantime, 7 bladder cancers were positive for both targets after double immunofluorescence staining with MAGE-A3 or A4 specific antibodies. The data presented here could be an important development in treatment protocols for pre-screening patients who are at risk. Our findings show that MAGE-A3 and MAGE-A4 can be both present in bladder cancer, suggesting that targeting both genes may be necessary for the success of immunotherapy treatment. Citation Format: Bailey Gilmore, Rachel Gonzalez, Aubrey Su, Dehe Kong, Eden Zewdu, Jina Yom, Tianli Qu, Zhaoying Guo, Xiaomin Hu, Qi Ren, Ranran Zhang, Eric Christenson, Yan Ma, Dezhong Yin, Patrick Yin, Wei Fu, Xuan Liu, Krishnan Allampallam. Colocalization of MAGE-A3 and MAGE-A4 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 999.